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Repetitive transcranial magnetic stimulation (rTMS), a noninvasive neuroregulatory technique used to treat neurodegenerative diseases, holds promise for spinocerebellar ataxia type 3 (SCA3) treatment, although its efficacy and mechanisms remain unclear. This study aims to observe the short-term impact of cerebellar rTMS on motor function in SCA3 patients and utilize resting-state functional magnetic resonance imaging (RS-fMRI) to assess potential therapeutic mechanisms. Twenty-two SCA3 patients were randomly assigned to receive actual rTMS (AC group, n  = 11, three men and eight women; age 32–55 years) or sham rTMS (SH group, n  = 11, three men and eight women; age 26–58 years). Both groups underwent cerebellar rTMS or sham rTMS daily for 15 days. The primary outcome measured was the ICARS scores and parameters for regional brain activity. Compared to baseline, ICARS scores decreased more significantly in the AC group than in the SH group after the 15-day intervention. Imaging indicators revealed increased Amplitude of Low Frequency Fluctuation (ALFF) values in the posterior cerebellar lobe and cerebellar tonsil following AC stimulation. This study suggests that rTMS enhances motor functions in SCA3 patients by modulating the excitability of specific brain regions and associated pathways, reinforcing the potential clinical utility of rTMS in SCA3 treatment. The Chinese Clinical Trial Registry identifier is ChiCTR1800020133.

Objective: Neuropathy is a well-recognized feature in spinocerebellar ataxia type 3 (SCA3) or Machado-Joseph disease (MJD), but the pattern of neuropathy is still a matter of debate. This study aimed to evaluate peripheral nerve involvement in MJD patients. Neurophysiological and clinical data were analyzed to distinguish neuronopathy from length-dependent distal axonopathy. Methods: In the present study we evaluated 26 patients with clinical and molecular-proven MJD and investigated their peripheral nerve involvement. Neurophysiological and clinical data were compared and correlated aiming to distinguish neuronopathy from distal axonopathy. Results: The neurophysiological evaluation showed that 42.3% of the patients had polyneuropathy. Among these patients, 81.8% presented neuronopathy. Conclusion: We concluded that neuronopathy is the most common form of peripheral nerve involvement in MJD patients.

Background Spinocerebellar ataxia type 3 (SCA3) is the most common subtype of SCA without effective treatment. This study aimed to evaluate the comparative efficacy of low-frequency repetitive transcranial magnetic stimulation (rTMS) and intermittent Theta Burst Stimulation (iTBS) in a larger cohort of SCA3 patients. Methods One hundred and twenty patients with SCA3 were randomly assigned to the 3 groups: 40 patients in the 1 Hz rTMS, 40 in the iTBS and 40 in the sham group. Patients underwent 10 sessions of rTMS targeting the cerebellum delivering for 5 consecutive days per week for 2 weeks (a total of 1200 pulses per session). Primary outcomes included the Scale for the Assessment and Rating of Ataxia (SARA) and the International Cooperative Ataxia Rating Scale (ICARS). Secondary outcomes included 10-m walking test (10MWT), nine-hole peg test (9-HPT), and PATA Rate Test (PRT). Outcome assessments were performed at baseline and on the last day of rTMS intervention. Results This study revealed that active rTMS outperformed sham in reducing the SARA and ICARS scores in SCA3 patients, but with no difference between the 1 Hz rTMS and iTBS protocol. Moreover, no significant differences were observed in SARA and ICARS scores between the mild and moderate to severe groups after the 1 Hz rTMS/iTBS therapy. Additionally, no severe adverse events were recorded in this study. Conclusions The study concluded that both 1 Hz rTMS and iTBS interventions targeting the cerebellum are effective to improve the symptoms of ataxia in patients with SCA3.

Aims Spinocerebellar ataxia type 3 (SCA3) is characterized by progressive neurodegeneration. This study aimed to map alterations in structural and functional connectivity (SC and FC) in SCA3 using network‐based statistics (NBS) and to explore the potential of transcranial magnetic stimulation (TMS) for modulating these aberrant networks and identifying novel therapeutic targets. Methods NBS was used to compare SC and FC between a large cohort of 117 SCA3 patients and 163 healthy controls (HCs). Partial correlation analysis examined the associations between altered connectivity and clinical variables (CAG repeat length, disease duration, and clinical scale scores). Additionally, paired t‐tests were used to evaluate longitudinal brain connectivity changes in 58 patients before and after TMS intervention to assess therapeutic effects. Results SCA3 patients exhibited a distinct disconnection–compensation pattern, characterized by significantly reduced SC and elevated FC within the subcortical (SUB), sensorimotor (SMN), and dorsal attention (DAN) networks. SC between the frontoparietal network (FPN) and SUB was abnormally increased and positively correlated with both disease duration and CAG repeat length, whereas intra‐SUB SC was negatively correlated with disease duration. Following TMS intervention, SC strength in two pathways that were abnormally enhanced at baseline was significantly attenuated. Conclusion Our findings reveal extensive connectome reorganization in SCA3. The correlations between SC abnormalities and clinical metrics, coupled with the modulatory effects of TMS, suggest that network‐based metrics can serve as biomarkers and guide the development of personalized neuromodulation strategies for SCA3. Trial Registration: (ChiCTR) 1800019901, 2000039434, 2500095738. This study identifies a dual pattern of structural and functional connectome disruption in SCA3 that correlates with clinical severity. Importantly, these abnormal structural connectivities are modulated by TMS, establishing them as promising imaging biomarkers and therapeutic targets for precision neuromodulation intervention.

Spinocerebellar ataxias (SCAs) are autosomal dominant genetic disorders characterized by progressive cerebellar degeneration and phenotypic variability. MJD/SCA3, the most prevalent form around the world and in Latin America, is also likely the most common hereditary ataxia in Uruguay. Despite its relevance, Uruguay lacks comprehensive epidemiological studies, and molecular diagnostics remain inaccessible in public health systems. This review provides a phenotypic description on genetically confirmed patients with MJD/SCA3 as a first step towards generating knowledge on this matter in our country. A retrospective review of 37 Uruguayan patients with suspected SCA was conducted. Sixteen patients with confirmed molecular diagnosis of MJD/SCA3 were included on this review. Data collected encompassed demographic information, genetic testing results, clinical manifestations, and imaging findings. Patients were evaluated at the Ataxias Polyclinic, Hospital de Clínicas, between 2019 and 2024 by the authors. Statistical analyses were performed using SPSS version 29.0. The mean age of symptom onset was 41.75 years, with gait ataxia as the initial symptom in 87.5% of cases. Clinical findings included appendicular ataxia (100%), dysarthria (90%), and oculomotor alterations (90%), with diverse deep sensitivity impairment in 62.5%. Genetic testing revealed an average of 72.9 CAG repeats in the ATXN3 gene. Cerebellar atrophy was observed in 75% of patients with MRI. Most had a diagnostic delay of 6.5 years and an autosomal dominant family history. Findings align with international descriptions of MJD/SCA3 while highlighting regional characteristics, including a potential genetic link with southern Brazil. The absence of dysautonomia, typically prevalent in MJD/SCA3, suggests underdiagnosis or insufficient evaluation. This study underscores the need for systematic clinical and molecular evaluations in Uruguay and serves as a foundation to understand hereditary ataxias at a national level. Further research is essential for improving diagnosis and management of this complex pathology.

Background Spinocerebellar ataxia type 3 (SCA3) is one of the most prevalent hereditary neurodegenerative disorders, with respiratory failure being the leading cause of mortality. Nevertheless, pulmonary function in SCA3 has not been thoroughly characterized, and the underlying mechanisms remain unclear. Methods We conducted pulmonary function tests in both patients and healthy controls, as well as in SCA3 mice and wild-type mice. In participants, we used diaphragm ultrasonography to evaluate diaphragmatic dysfunction. We examined clinical features and inflammatory biomarkers to identify independent associations with pulmonary function. We also performed histopathological and immunohistochemical analyses on lung tissues from SCA3 mice to assess the presence of chronic airway inflammation. Results We enrolled 102 patients and 91 healthy controls for pulmonary function testing. For blood biomarker analyses, SCA3 participants with available blood data were drawn from the same patient cohort and were compared with an independent cohort of 88 age- and sex-matched healthy controls, distinct from the pulmonary-function controls. Compared with controls, patients showed significant reductions in FVC ( P  < 0.001), FEV1 ( P  < 0.001), DLco-SB ( P  = 0.015), and small-airway flow indices ( P  < 0.05), along with an increased RV/TLC ratio ( P  < 0.001), indicating subclinical pulmonary dysfunction. Impaired pulmonary function, defined according to prespecified criteria, was identified in 71/102 (69.6%) patients versus 0/91 controls ( P  < 0.001). Pulmonary impairment was associated with ataxia severity (SARA: OR = 1.196, 95% CI 1.038–1.376; P  = 0.013). Diaphragm ultrasound showed preserved diaphragmatic function, whereas systemic inflammatory markers were associated with reduced pulmonary function, with NLR inversely correlated with MEF25 (ρ =–0.272, P  = 0.010). In SCA3 mice ( n  = 4) compared with wild-type mice ( n  = 3), pulmonary function abnormalities and lung pathology were consistent with airway inflammatory changes. Conclusion SCA3 is associated with early, subclinical pulmonary dysfunction that worsens with disease progression. Chronic inflammation in the small airways may be involved in this process. Our findings underscore the need for early intervention with chest physiotherapy and respiratory training as part of the clinical management of SCA3.

Neurodegenerative diseases, including polyglutamine diseases, remain a clinical challenge, partly because of limited animal models that recapitulate human disease. Here, we describe a second-generation transgenic marmoset model of spinocerebellar ataxia 3 (SCA3), a polyglutamine disease, which stably expresses expanded CAG repeats in ataxin 3 (ATXN3). All five offspring of the founder marmoset harbored the transgene with reduced transgene integration sites compared with the founder and without repeat instability or genetic mosaicism, offering improved construct validity. Three of the five marmosets developed progressive motor impairments that segregated into two distinct phenotypes – early onset with rapid progression and late onset with mild progression – accompanied by corresponding patterns in body weight gain and grip strength. Pathological analysis revealed cerebellar Purkinje cell loss, spinal cord neurodegeneration and widespread intranuclear inclusions. The severity of motor phenotypes correlated with transgene expression levels in disease-relevant brain regions, including the cerebellum and spinal cord. By overcoming the translational limitations of rodent systems, our second-generation model offers a powerful platform for investigating disease mechanisms and testing potential therapeutics, advancing the utility of transgenic marmosets as clinically relevant models of neurodegenerative diseases.

Background Spinocerebellar ataxia type 3 (SCA3) is a hereditary disease caused by abnormally expanded CAG repeats in the ATXN3 gene. The study aimed to identify potential biomarkers for assessing therapeutic efficacy by investigating the associations between expanded CAG repeat size, brain and spinal cord volume loss, and motor functions in patients with SCA3. Methods In this prospective, cross-observational study, we analyzed 3D T1-weighted MRIs from 92 patients with SCA3 and 42 healthy controls using voxel-based morphometry and region of interest approaches. Associations between expanded CAG repeat size, brain and spinal cord volume loss, and International Cooperative Ataxia Rating Scale (ICARS) scores were investigated using partial correlation and mediation analyses. Sample sizes of potential biomarkers were calculated. Results Compared with healthy controls, SCA3 patients had lower cerebellar volume and cervical spinal cord area. SCA3 patients evolved along a stage-independent decline that began in the cerebellum, progressed to spinal cord, brainstem, thalami, and basal ganglia, and extensive subcortex. Expanded CAG repeat size was associated with right cerebellar lobule IV volume ( r  = − 0.423, P  < 0.001) and cervical spinal cord area ( r  = − 0.405, P  < 0.001), and higher ICARS ( r  = 0.416, P  < 0.001). Mediation analysis revealed an indirect effect of expanded CAG repeat size on ICARS through spinal cord. Sample sizes estimation revealed that a minimum sample size was achieved with spinal cord measures. Conclusions Our results indicate the potential of cervical spinal cord area as a biomarker for disease progression and a minimum sample size estimation in future clinical studies of SCA3.

Machado-Joseph disease (MJD) or spinocerebellar ataxia type 3 (SCA3) is an autosomal dominantly-inherited neurodegenerative disorder caused by the over-repetition of a CAG codon in the MJD1 gene. This expansion translates into a polyglutamine tract that confers a toxic gain-of-function to the mutant protein--ataxin-3, leading to neurodegeneration in specific brain regions, with particular severity in the cerebellum. No treatment able to modify the disease progression is available. However, gene silencing by RNA interference has shown promising results. Therefore, in this study we investigated whether lentiviral-mediated allele-specific silencing of the mutant ataxin-3 gene, after disease onset, would rescue the motor behavior deficits and neuropathological features in a severely impaired transgenic mouse model of MJD. For this purpose, we injected lentiviral vectors encoding allele-specific silencing-sequences (shAtx3) into the cerebellum of diseased transgenic mice expressing the targeted C-variant of mutant ataxin-3 present in 70% of MJD patients. This variation permits to discriminate between the wild-type and mutant forms, maintaining the normal function of the wild-type allele and silencing only the mutant form. Quantitative analysis of rotarod performance, footprint and activity patterns revealed significant and robust alleviation of gait, balance (average 3-fold increase of rotarod test time), locomotor and exploratory activity impairments in shAtx3-injected mice, as compared to control ones injected with shGFP. An important improvement of neuropathology was also observed, regarding the number of intranuclear inclusions, calbindin and DARPP-32 immunoreactivity, fluorojade B and Golgi staining and molecular and granular layers thickness. These data demonstrate for the first time the efficacy of gene silencing in blocking the MJD-associated motor-behavior and neuropathological abnormalities after the onset of the disease, supporting the use of this strategy for therapy of MJD.

Tremor is a common movement disorder associated with several neurodegenerative diseases, yet its mechanisms are not well understood. Using a machine-learning method, Feature Learning-based Leg segmentation and Tracking (FLLIT), we previously characterised gait and tremor signatures in a Drosophila model for spinocerebellar ataxia 3 (SCA3) and found them to be analogous to those in human SCA3. Here, we carried out a functional screen for neuronal populations that underlie tremor and found that dysfunction of a specific population of neurons in the ventral nerve cord (VNC) is necessary and sufficient for tremor. Adult-onset expression of mutant ATXN3 in, or genetic hypo-activation of, these neurons led to tremor, indicating their important role in adult motor control. RNA-sequencing and functional experiments showed that dysfunction of GABAergic neurons, and not that of other neurotransmitter populations tested, causes tremor. Finally, we identified a small subset of ∼30 predominantly GABAergic neurons within the adult VNC that are essential for smooth walking. This study demonstrates that tremor in SCA3 flies arises from GABAergic dysfunction, and that FLLIT can be used to dissect motor control mechanisms.